The present invention relates to identifying one or more genetic markers which correlate with improved success in reducing blood pressure levels in hypertensive individuals.
Studies have shown that individuals suffering from hypertension can alleviate symptoms or otherwise improve their conditions through exercise. Unfortunately, some individuals, no matter how rigorously they exercise, are unable to improve their conditions, while others benefit to a much greater extent than predicted. These results underscore the fact that many factors contribute to an individual""s well-being. Such factors include, for example, behaviors such as diet and exercise, genetic makeup, and environment. While behavior and environment can be controlled, altered or regulated, an individual""s genetic makeup is essentially predetermined and set at birth. The present inventors hypothesized that upon identifying the genetic makeup of a hypertensive population and observing that some individuals of the population lower their blood pressure from a change of behavior to a much greater or lesser extent than expected, a correlation could be made between the presence or absence of certain genetic markers and success in reducing blood pressure levels.
An object of the present invention is to identify one or more genetic markers which positively correlate with improved success in reducing blood pressure levels in hypertensive individuals.
The present inventors have discovered a number of genetic markers which positively correlate with improved success in reducing blood pressure levels in hypertensive individuals, as compared with other genetic makeup at the same gene loci. Therefore, the present invention is directed to a method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:
identifying a subject having an allele and/or genotype at a particular gene locus which positively correlates with improved success in reducing blood pressure levels in hypertensive individuals, as compared with other alleles and/or genotypes at the same gene locus, wherein the subject is in need of reduced blood pressure levels, and
engaging the subject in exercise training for a period of time sufficient to reduce blood pressure levels in the subject.
The inventors have found that a number of genetic markers positively correlate with improved success in reducing blood pressure levels in hypertensive individuals, as compared with other genetic makeup at the same gene loci. Markers which the inventors have investigated include the lipoprotein lipase (LPL) gene PvuII and HindIII restriction sites, the angiotensin converting enzyme (ACE) gene insertion site, and the angiotensinogen M235T site.
The term xe2x80x9cblood pressurexe2x80x9d includes systolic blood pressure, diastolic blood pressure and mean blood pressure. A xe2x80x9creduction in blood pressurexe2x80x9d may mean a reduction in systolic blood pressure and/or diastolic blood pressure and/or mean blood pressure. Such a reduction may include daytime blood pressure and/or nighttime blood pressure, or the reduction may be unrelated to time of day.
The term xe2x80x9csingle course of exercisexe2x80x9d, as used throughout this application, means a cardiovascular exercise session of any type which is conducted during one day. An exercise session may comprise an aerobics class, treadmill training, step machine, or any other suitable cardiovascular exercise regimen. For most cases, exercise may be completed in, for example, 30 minutes to 3 hours, with optional brief rest periods of 3-15 minutes, however this amount would vary depending on the health and endurance of the subject.
The term xe2x80x9cextensive exercisexe2x80x9d means about 10 single courses of exercise or more, preferably at least 15, at least 20, or at least 25 single courses of exercise, over a defined period of time (xe2x80x9cthe exercise periodxe2x80x9d). The exercise period in the case of an extensive exercise protocol may be from about 30-400 days, preferably from about 50-350 days or 70-300 days.
The term xe2x80x9climited exercisexe2x80x9d means about 5 single courses of exercise or less, preferably at most 3, or 1 single course of exercise, over the exercise period. The exercise period in the case of a limited exercise protocol may be about 12 days or less, preferably at most 10, at most 7, or at most 5 days. It is most preferred that the limited exercise period be at most 3 days.
The term xe2x80x9cmoderate exercisexe2x80x9d means about 5-9 single courses of exercise, preferably about 6-8, or 7 single courses of exercise, over the exercise period. The exercise period in the case of a limited exercise protocol may be from about 5-50 days, preferably from about 5-30 days, 5-20 days, or 5-15 days.
The time between exercise periods depends on whether the exercise period is an extensive, limited or moderate exercise period. In the case of extensive exercise periods, the time between exercise periods may be from about 10-120 days or more. In the case of limited exercise periods, the time between exercise periods may be from 4-60 days or more. In the case of moderate exercise periods, the time between exercise periods may be from 6-90 days or more. The term xe2x80x9cbetween exercise periodsxe2x80x9d means that time during which the subject is not in an extensive, limited or moderate exercise program.
Lipoprotein lipase (LPL) is an enzyme that catalyzes the breakdown of triglycerides in the plasma to release free fatty acids. This hydrolysis also influences the metabolism of circulating lipoproteins. LPL has also been shown to enhance the triglyceride-rich chylomicron binding to low-density lipoprotein receptor-related proteins. Thus, LPL may also be an important regulator of chylomicron metabolism. The LPL gene is located on human chromosome 8p22. It is approximately 35 kilobases long and has 10 functionally differentiated exons. Two primary polymorphic variations occur at the LPL gene locus in frequencies that are important on a population basis. These two variations are detected by PvuII and HindIII restriction sites. There are three genotypes at each site, with the alleles for both PvuII and HindIII restriction sites denoted as xe2x80x9c+xe2x80x9d or xe2x80x9cxe2x88x92xe2x80x9d, based on the presence or absence of a restriction site on that allele at the LPL locus with PvuII or HindIII. Thus, for both PvuII and HindIII there are three genotypes: +/+, +/xe2x88x92 and xe2x88x92/xe2x88x92.
The present inventors have discovered that hypertensive individuals with different PvuII genotypes exhibit different degrees of success in reducing their blood pressure levels through exercise. These results could not have been predicted from initial patient screening.
The inventors have surprisingly discovered that each PvuII genotype potentially can benefit from exercise, however, the amount of exercise which produces the most benefits varies according to genotype. Specifically, the inventors have found that subjects having a xe2x80x9c+/+xe2x80x9d genotype for a PvuII restriction site exhibit more reduction in blood pressure levels than those with xe2x80x9c+/xe2x88x92xe2x80x9d or xe2x80x9cxe2x88x92/xe2x88x92xe2x80x9d genotypes, after extensive exercise. However, those subjects having xe2x80x9c+/xe2x88x92xe2x80x9d or xe2x80x9cxe2x88x92/xe2x88x92xe2x80x9d genotypes exhibit more reduction in blood pressure levels than those with xe2x80x9c+/+xe2x80x9d genotypes, after limited exercise.
Therefore, one method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9c+/+xe2x80x9d genotype for a PvuII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having at least one xe2x80x9cxe2x88x92xe2x80x9d allele or a xe2x80x9c+/xe2x88x92xe2x80x9d or xe2x80x9cxe2x88x92/xe2x88x92xe2x80x9d genotype for a PvuII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
The present inventors have also discovered that hypertensive individuals with different HindIII genotypes exhibit different degrees of success in reducing their blood pressure levels through exercise. These results could not have been predicted from initial patient screening.
The inventors have found that those individuals having xe2x80x9c+/+xe2x80x9d or xe2x80x9c+/xe2x88x92xe2x80x9d genotype for a HindIII restriction site exhibit more reduction in blood pressure levels than those with xe2x80x9cxe2x88x92/xe2x88x92xe2x80x9d genotypes, after extensive exercise. In addition, those subjects having xe2x80x9c+/xe2x88x92xe2x80x9d genotypes exhibit more reduction in blood pressure levels than those with xe2x80x9c+/+xe2x80x9d genotypes, after limited exercise.
Therefore, an additional method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having at least one xe2x80x9c+xe2x80x9d allele or a xe2x80x9c+/+xe2x80x9d or xe2x80x9c+/xe2x88x92xe2x80x9d genotype for a HindIII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9c+/xe2x88x92xe2x80x9d genotype for a HindIII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
Angiotensin converting enzyme (ACE) is the enzyme responsible for catalyzing the conversion of angiotensin I, a relatively inactive tissue and plasma vasopressor hormone, into the potent and highly active vasopressor hormone angiotensin II. This cascade of reactions is part of the renin-angiotensin-aldosterone system that has long been known to be an important regulator of arteriolar relaxation and vasoconstriction, and hence blood pressure, in humans and animals. The ACE gene is polymorphic with two common alleles designated xe2x80x9cIxe2x80x9d and xe2x80x9cDxe2x80x9d, resulting in three genotypes: xe2x80x9cI/Ixe2x80x9d, xe2x80x9cI/Dxe2x80x9d and xe2x80x9cD/Dxe2x80x9d. The xe2x80x9cDxe2x80x9d allele has a 287-base pair marker in intron 16 of the ACE gene deleted, whereas the xe2x80x9cIxe2x80x9d allele has the 287-base pair marker inserted. The xe2x80x9cDxe2x80x9d allele is associated with increased levels of ACE in both plasma and ventricular tissues. Increased levels of ACE will clearly contribute to increased myocardial and vascular smooth muscle growth and increased arteriolar vasoconstriction. Thus, the presence of the xe2x80x9cDxe2x80x9d allele is hypothesized to have deleterious effects on the cardiovascular system, and, in fact, the xe2x80x9cDxe2x80x9d allele has been associated with increased risk of left ventricular hypertrophy, cardiovascular disease, and sudden cardiovascular death.
The present inventors have discovered that hypertensive individuals with different ACE genotypes exhibit different degrees of success in reducing their blood pressure levels through exercise. These results could not have been predicted from initial patient screening.
The inventors have found that those individuals having xe2x80x9cI/Ixe2x80x9d or xe2x80x9cI/Dxe2x80x9d genotype for an ACE gene exhibit more reduction in blood pressure levels than those with xe2x80x9cD/Dxe2x80x9d genotypes, after extensive exercise. However, those subjects having xe2x80x9cI/Ixe2x80x9d or xe2x80x9cD/Dxe2x80x9d genotypes exhibit more reduction in blood pressure levels than those with xe2x80x9cI/Dxe2x80x9d genotypes, after limited exercise. In addition, those subjects having xe2x80x9cI/Ixe2x80x9d genotypes exhibit more reduction in blood pressure levels than those with xe2x80x9cI/Dxe2x80x9d or xe2x80x9cD/Dxe2x80x9d genotypes, after moderate exercise.
Therefore, an additional method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having at least one xe2x80x9cIxe2x80x9d allele or an xe2x80x9cI/Ixe2x80x9d or xe2x80x9cI/Dxe2x80x9d genotype for an ACE gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9cI/Ixe2x80x9d or xe2x80x9cD/Dxe2x80x9d genotype for an ACE gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
Yet another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9cI/Ixe2x80x9d genotype for an ACE gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in moderate exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
Angiotensinogen (AGT) is the circulating protein substrate from which renin cleaves angiotensin I. AGT in the circulation originates in the liver. Human AGT is a glycoprotein with a molecular weight of approximately 57,000.
The method of the invention uses genetic variations at the M235T site (amino acid at position 235 changed from methionine (AUG) to threonine (ACG)) at the AGT gene locus to identify hypertensive persons who will reduce their blood pressure with exercise training. The inventors have found that hypertensives homozygous for either the xe2x80x9cTxe2x80x9d or the xe2x80x9cMxe2x80x9d allele decrease blood pressure more with extensive exercise training than those heterozygous at this loci. Hypertensives with the AGT xe2x80x9cT/Txe2x80x9d genotype decrease their systolic blood pressure more than those with the xe2x80x9cM/Mxe2x80x9d or xe2x80x9cM/Txe2x80x9d genotype, while hypertensives with xe2x80x9cM/Mxe2x80x9d genotype decrease their diastolic blood pressure more than those with the xe2x80x9cT/Txe2x80x9d or xe2x80x9cM/Txe2x80x9d genotype, with extensive exercise. In addition, those subjects having xe2x80x9cT/Txe2x80x9d genotype exhibit more reduction in blood pressure levels than those with xe2x80x9cM/Txe2x80x9d genotype, after limited exercise.
Therefore, a method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9cT/Txe2x80x9d or xe2x80x9cM/Mxe2x80x9d genotype for an AGT gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.
A method of reducing systolic blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9cT/Txe2x80x9d genotype for an AGT gene, wherein the subject is in need of reduced systolic blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the systolic blood pressure levels in the subject.
A method of reducing diastolic blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9cM/Mxe2x80x9d genotype for an AGT gene, wherein the subject is in need of reduced diastolic blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the diastolic blood pressure levels in the subject.
Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a xe2x80x9cT/Txe2x80x9d genotype for an AGT gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.